The aims of this project are to apply genetic approaches to elucidate the molecular mechanisms underlying vesicoureteral reflux (VUR). VUR occurs in about 1 % of infants and is caused by malfunction of the vesicoureteral junction, resulting in retrograde flow of urine from the bladder into the kidneys. VUR accounts for up to 25% of cases of end stage renal disease (ESRD) in children. Familial aggregation of VUR suggests that genetic factors are important in the development of this disorder. To date, we have recruited nine large kindreds with VUR; these kindreds demonstrate transmission consistent with autosomal dominant inheritance with reduced penetrance. In these pedigrees, we have excluded linkage to candidate genes and intervals reported to date, such as the VUR1 locus on chromosome 1 p13 or the ROBO2 gene on chromosome 3p12. Power analysis demonstrates that these nine kindreds can detect linkage with a maximal expected lod score of 21.4 under genetic homogeneity; they can also achieve genome-wide significance even if only 33% of kindreds are linked to a given locus (maximal expected lod score with 33% locus heterogeneity = 4.7). Moreover, three of these kindreds are sufficiently large to each achieve a lod score >3 with affected only-analysis and can therefore independently identify a locus with genome-wide significance. In the current proposal, we will characterize and recruit a total of 30 kindreds with VUR and 200 patients with sporadic VUR to enable clinical and genetic studies. We will perform a genome-wide search to localize the VUR genes on the genetic map, and next proceed to gene annotation and identification of the gene(s) underlying the linkage interval(s). Identification of the gene(s) for VUR will provide insight in the biology of ureter and bladder development. Moreover, it will provide the opportunity to develop novel diagnostic and therapeutic tools for this common clinical disorder. This project is relevant to public health because VUR is one of the most common causes of pediatric renal failure, resulting in significant childhood morbidity and mortality. Identification of genes underlying VUR will provide novel approaches to detect patients at risk and may enable the development of novel therapeutic approaches for this disorder [unreadable] [unreadable]